Cryo-EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms

Le Thi My Le, James Robert Thompson, Sepehr Dehghani-Ghahnaviyeh, Shashank Pant, Phuoc Xuan Dang, Jarrod Bradley French, Takahisa Kanikeyo, Emad Tajkhorshid, Amer Alam

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of the underlying substrate interactions and transport mechanisms remain poorly resolved at the molecular level. Here we report cryo-EM structures of lipid-embedded human ABCA7 in an open state and in a nucleotide-bound, closed state at resolutions between 3.6 and 4.0 Å. The former reveals an ordered patch of bilayer lipids traversing the transmembrane domain (TMD), while the latter reveals a lipid-free, closed TMD with a small extracellular opening. These structures offer a structural framework for both substrate entry and exit from the ABCA7 TMD and highlight conserved rigid-body motions that underlie the associated conformational transitions. Combined with functional analysis and molecular dynamics (MD) simulations, our data also shed light on lipid partitioning into the ABCA7 TMD and localized membrane perturbations that underlie ABCA7 function and have broader implications for other ABCA family transporters.

Original languageEnglish (US)
Article numbere111065
JournalEMBO Journal
Volume42
Issue number3
DOIs
StatePublished - Feb 1 2023

Bibliographical note

Funding Information:
We would like to thank Dr. Kaspar Locher at ETH, Zurich, Switzerland, for providing the synthetic gene construct of ABCA7. We would also like to thank the cryo‐EM and shared instruments core facilities at the Hormel Institute for help with experimental setup, and Dr. Rhoderick Brown, Dr. Jeppe Olsen, and Dr. Devanshu Kurre for critical reading and discussion during manuscript preparation. This work was supported in part by the Hormel Foundation (Institutional research funds to AA), the National Institutes of Health (NIH) award 1R21‐AG069180‐01A1 (to AA), NIH award R35GM124898 (to JBF), and the Cure Alzheimer's fund (to TK). The computational component of the project was supported by the NIH awards P41‐GM104601 (to ET) and R01‐GM123455 (to ET). We also acknowledge computing resources provided by Blue Waters at National Center for Supercomputing Applications (NCSA), by eXtreme Science and Engineering Discovery Environment (XSEDE) (grant MCA06N060 to ET), and by Microsoft Azure.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Keywords

  • ABCA7
  • Alzheimer's disease
  • cryo-EM
  • exporter
  • flippase

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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